RESEARCH PROJECT 1 HIGHLY-INTEGRATED ULTRASMALL AND BRIGHT FLUORESCENT SILICA PARTICLE ARCHITECTURES OF VARYING SIZE, GEOMETRY, AND COMPOSITION FOR CANCER DIAGNOSTICS AND THERAPEUTICS 1. Project Abstract/Summary The overarching goal of this basic research/discovery project (RP1) is to first explore and then optimize novel classes of ultrasmall (<10 nm) fluorescent core-shell silica nanoparticles (NPs) and rings (C'/AC' dots and C rings) that are synthesized in water and used as targeted diagnostic and therapeutic probes to detect and treat various types of cancer, in particular melanoma. A specific goal of this project is to investigate alterations in pharmacokinetics (PK), renal clearance, and tumor-to-background ratios in human melanoma (M21) xenograft models as a function of size (~6-15nm, i.e. around the cut off of ~10 nm for renal clearance), shape (spheres, rings), and surface chemistry (ligand number). Major milestones of the project include comprehensive particle characterization using an array of imaging, scattering, and spectroscopic techniques. Rather than studying biological properties solely on the basis of batch-to-batch variations in average particle properties, RP1 will employ a combination of high-resolution analytical tools (GPC and HPLC) to analyze and separate different fractions from individual particle synthesis batches. A specific goal of RP1 is to address one of the most fundamental, yet unresolved, problems of nanomaterials interactions with biological systems - namely the question of how material heterogeneity, in the form of batch-to-batch variations and variations within a batch, in particle size distributions and surface composition, modulates PK, clearance profiles, and target-to-background ratios. Particle outcomes of this RP1 will feed into all other RPs2-4 thereby covering the entire diagnostic and therapeutic map of the Center.